Meta-bromination reactions of benzoyl halides are integral reactions in the production of a variety of widely used pharmaceutical compounds, and as such, they are reactions of considerable commercial importance. As an example of the utility of this reaction, it can be used to prepare meta-bromobenzoyl chloride, which is an intermediate in the production of ketoprofen drugs, a commonly-prescribed class of pain relievers.
It has long been known that bromine chloride is an effective bromination agent for a diverse group of aromatic substrates. In addition to brominating benzoyl halides, it has also been used to brominate toluene, anisole, substituted biphenyl compounds, and other aromatic compounds. In the case of benzoyl halides, metabromination with bromine chloride is more effective than with bromine itself, and is thus deemed particularly advantageous.
However, the preparation and procurement of bromine chloride can be difficult in that bromine chloride is quite unstable. Once prepared, it readily decomposes into bromine and chlorine, even at relatively low temperatures, such as room temperature. Because of this characteristic, when brominating at temperatures which are higher than room temperature, it is often necessary to supply bromine chloride to the reaction at a relatively high rate in order to have sufficient bromine chloride in the reaction mixture to obtain effective bromination, and much bromine chloride is often wasted in the process.
In spite of the above-described difficulties, metabromination of benzoyl halides with bromine chloride is still performed at temperatures which are significantly higher than room temperature. There are several reasons for such a practice.
First, attempts to brominate a benzoyl halide at low temperatures can be problematic. Unlike processes for the bromine chloride bromination of other aromatic compounds, such as toluene and anisole, which proceed readily at temperatures of about 0.degree. C. and below, the metabromination reaction of benzoyl halides with bromine chloride can be impeded by such temperatures yielding significantly less metabrominated product than can be achieved at higher temperatures.
In addition, the use of high temperatures in the bromination of benzoyl bromides with bromine chloride has a basis in the teachings of elementary organic chemistry coupled with the experience gained in brominating other aromatic compounds. Without desiring to be bound by theory, the relationship between ring bromination rate and reaction temperature can be understood in light of the following reasoning. It has been observed that substituents on the aromatic ring which are "electron-donating" also generally engender ease of bromination at low temperatures. Such an effect can be explained by the logical conclusion that these substituents readily increase the electron density on the aromatic ring via an "electron-donating" effect. Such increased electron density facilitates the electrophilic addition of bromine. Accordingly, compounds such as toluene, anisole and others which bear "electron-donating" substituents on the aromatic ring, should require only moderate temperatures in order to undergo efficient bromination. By further application of this reasoning, the bromination of benzoyl halides, as well the bromination of other aromatic compounds which similarly bear "electron-withdrawing" substituents on their aromatic rings, should require higher temperatures in order to undergo efficient bromination (see, for example, U.S. Pat. No. 2,607,802 to Britton et al.). Hence the use of high temperatures.
In addition to the decomposition of bromine chloride at reaction temperatures often used in the bromination of benzoyl halides with bromine chloride, a second problem encountered in the fore-mentioned bromination reaction is the concomitant formation of p-bromobenzoyl halide. For example, known methods for the bromine chloride meta-bromination of benzoyl chloride often yield as much as approximately two percent p-bromobenzoyl chloride. The competitive side reaction which produces the para-isomer also diminishes the purity and yield of the metabrominated product. The presence of the para-isomer has yet another undesirable consequence in that its removal from the meta-isomer is particularly difficult since the similarity in boiling points of the isomers can limit the effectiveness of conventional separation methods such as distillation.
A process for the bromine chloride metabromination of benzoyl chloride which surmounts the problem of bromine chloride instability at high temperatures, which forms parabromobenzoyl chloride in lower weight percent than obtained in currently-practiced processes, and yet proceeds with a reaction rate similar to that observed with bromine chloride at high temperatures would represent a significant improvement in the state of the art.